By Salynn Boyles From MedPage Today

Patch mimicking beta-cell function could offer ‘closed-loop’ insulin delivery

Note that this diabetic mouse study demonstrated that a novel glucose-sensing, insulin-releasing patch controlled blood sugar levels well.

Obviously, many more studies will be needed before human tests can begin.

A “smart” patch containing hundreds of insulin-delivering microneedles was found to effectively regulate blood glucose levels in a type 1 diabetes mouse model, and researchers said the device could prove to be a simple closed-loop strategy for treating diabetes.

In a study published online in PNAS Early Edition, researcher Zhen Gu, PhD, and colleagues demonstrated what they believe to be the first enzyme-based, glucose-responsive insulin-delivery patch device that uses sensitivity to hypoxia instead of pH variance. Gu is an assistant professor with the Joint Department of Biomedical Engineering at the University of North Carolina Chapel Hill and NC State University Raleigh.

The square patch, which is about the size of a penny, was covered with more than 100 tiny needles packed with insulin and the glucose-sensing enzyme glucose oxidase.

“This smart insulin patch with its novel trigger mechanism offers a clinical opportunity for closed-loop delivery of insulin in a fast glucose-responsive, pain-free, and safe manner,” the researchers wrote, adding that the delivery system may also prove useful in the treatment of other diseases.

Simple Closed-Loop Insulin Delivery

In a telephone interview, Gu told MedPage Today that while several closed-loop insulin-delivery systems appear promising, these systems require mechanical sensors and pumps, with insulin delivered via needle-tipped catheters. An artificial pancreas strategy that combines fast responsiveness, ease of administration, and adequate biocompatability remains a challenge, he said.

Gu and colleagues sought to mimic beta-cell activity with a patch that would serve as a blood glucose sensor, while also storing and releasing the right amount of insulin into the blood when needed.

Combining hyaluronic acid (HA) and 2-nitroimidazole (NI), which can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions, resulted in a new molecule that was hydrophilic on one end and hydrophobic on the other. A mix of these molecules self-assembled into tiny vesicles with the hydrophobic ends pointing inward and the hydrophilic ends pointing out.

The self-assembled hypoxia-sensitive hyaluronic acid (HS-HA) vesicles — each 100 times smaller than the width of a human hair — were filled with insulin and the glucose detecting enzyme glucose oxidase, which can convert glucose to gluconic acid in the presence of oxygen.

“Instead of using enzymatically induced pH changes, for the first time to our knowledge we have taken advantage of the local generation of hypoxia due to the consumption of oxygen in the enzymatic reaction as a trigger for rapid insulin release in response to hyperglycemia,” the researchers wrote.

In lab experiments, excess glucose was found to gravitate to the artificial vesicles when glucose levels rose and the enzymes converted the glucose into gluconic acid, which promoted hypoxia. This, in turn, turned the hydrophobic NI molecules hydrophilic, causing the vesicles to send insulin into the bloodstream.

Human Patch Would Be a ‘Game Changer’

Gu and colleagues then created a microneedle patch delivery device, using hyaluronic acid in a rigid form stiff enough to pierce the skin. One hundred of these microneedles were placed on a thin silicon strip.

“The framework of both needle patches and vesicles was made from hyaluronic acid, which is highly biocompatible,” Gu said.

In the type 1 diabetes mouse model, the patch was found to control blood glucose levels better than a standard injection of insulin with less risk of inducing hypoglycemia.

“The results of serial administration with microneedles showed that it could precisely control glucose in a normal range for prolonged periods,” the researchers wrote. “Also, considering that mice have reduced sensitivity to the human insulin used in this study, the real dose for potential human use will be significantly lower.”

“The hard part of diabetes care is not the insulin shots, or the blood sugar checks, or the diet but the fact that you have to do them all several times a day, every day for the rest of your life,” study co-author John Buse, MD, PhD, of the University of North Carolina Diabetes Care Center said in a written press statement. Buse is a past president of the American Diabetes Association.

“If we can get these patches to work in people, it will be a game changer,” he added.

The research was funded by the NC TraCS Institute and the American Diabetes Association.

For more on this story go to: http://www.medpagetoday.com/Endocrinology/Type1Diabetes/52342